3 β-hydroxysteroid-Δ 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by endoplasmic reticulum (ER) stress.

Abstract

3β-Hydroxysteroid-Δ24 reductase (DHCR24) is an endoplasmic reticulum (ER)-localized multifunctional enzyme that possesses anti-apoptotic and cholesterol-synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc-tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ-infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress.

• Authors: Xiuli Lu, Yang Li, Weiqi Wang, Shuchao Chen, Ting Liu, Dan Jia, Xiaoping Quan, Deliang Sun, Alan K Chang, Bing Gao
• Journal: PloS one (PLoS One) Vol. 9 Issue 1 Pg. e86753 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24489783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 1
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• IGF1 protein, human
• Nerve Tissue Proteins
• Reactive Oxygen Species
• Recombinant Fusion Proteins
• Tunicamycin
• Transcription Factor CHOP
• Insulin-Like Growth Factor I
• Cholesterol
• Oxidoreductases Acting on CH-CH Group Donors
• DHCR24 protein, human
• EIF2AK3 protein, human
• eIF-2 Kinase
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Caspase 12

Topics

• Adenoviridae (genetics)
• Apoptosis (drug effects)
• Caspase 12 (genetics, metabolism)
• Caveolin 1 (genetics, metabolism)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Cytoprotection
• DNA Fragmentation (drug effects)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects, genetics)
• Gene Expression
• Genetic Vectors
• Heat-Shock Proteins (genetics, metabolism)
• Humans
• Insulin-Like Growth Factor I (genetics, metabolism)
• MAP Kinase Kinase 4 (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (cytology, drug effects, enzymology)
• Oxidoreductases Acting on CH-CH Group Donors (genetics, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Transcription Factor CHOP (genetics, metabolism)
• Tunicamycin (pharmacology)
• eIF-2 Kinase (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)